EP1569914A1 - Pyrimidine-sulfamides and their use as endothelian receptor antagonist - Google Patents
Pyrimidine-sulfamides and their use as endothelian receptor antagonistInfo
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- EP1569914A1 EP1569914A1 EP03778307A EP03778307A EP1569914A1 EP 1569914 A1 EP1569914 A1 EP 1569914A1 EP 03778307 A EP03778307 A EP 03778307A EP 03778307 A EP03778307 A EP 03778307A EP 1569914 A1 EP1569914 A1 EP 1569914A1
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- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
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- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/56—One oxygen atom and one sulfur atom
Definitions
- the present invention relates to novel pyrimidine-sulfamides of the general formula I and their use as active ingredients in the preparation of pharmaceutical compositions.
- the invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more compounds of the general formula I, and especially their use as endothelin receptor antagonists.
- Endothelins are 21-amino acid peptides produced and active in almost all tissues (Yanagisawa M et al.: Nature (1988) 332:411 ). Endothelins are potent vasoconstrictors and important mediators of cardiac, renal, endocrine and immune functions (McMillen MA et al.: J Am Coll Surg (1995) 180:621 ). They participate in bronchoconstriction and regulate neurotransmitter release, activation of inflammatory cells, fibrosis, cell proliferation and cell differentiation (Rubanyi GM et al.: Pharmacol Rev (1994) 46:328).
- ET A , ET B Two endothelin receptors have been cloned and characterized in mammals (ET A , ET B ) (Arai H et al.: Nature (1990) 348:730; Sakurai T et al.: Nature (1990) 348:732).
- the ET A receptor is characterized by higher affinity for ET-1 and ET-2 than for ET-3. It is predominant in vascular smooth muscle cells and mediates vasoconstricting and proliferative responses (Ohlstein EH et al.: Drug Dev Res (1993) 29:108).
- the ET B receptor has equivalent affinity for the three endothelin isopeptides and binds the linear form of endothelin, tetra-ala- endothelin, and sarafotoxin S6C (Ogawa Y et al.: BBRC (1991 ) 178:248).
- This receptor is located in the vascular endothelium and smooth muscles, and is also particularly abundant in lung and brain.
- the ETB receptor from endothelial cells mediates transient vasodilator responses to ET-1 and ET-3 through the release of nitric oxide and/or prostacyclin whereas the ET B receptor from smooth muscle cells exerts vasoconstricting actions (Sumner MJ et al.: Brit J Pharmacol (1992) 107:858).
- ETA and ET B receptors are highly similar in structure and belong to the superfamily of G-protein coupled receptors.
- ET-1 A pathophysiological role has been suggested for ET-1 in view of its increased plasma and tissue levels in several disease states such as hypertension, pulmonary hypertension, sepsis, atherosclerosis, acute myocardial infarction, congestive heart failure, renal failure, migraine and asthma.
- endothelin receptor antagonists have been studied extensively as potential therapeutic agents. Endothelin receptor antagonists have demonstrated preclinical and/or clinical efficacy in various diseases such as cerebral vasospasm following subarachnoid hemorrhage, heart failure, pulmonary and systemic hypertension, neurogenic inflammation, renal failure and myocardial infarction.
- membranes of CHO cells expressing human recombinant ETA or ETB receptors were used.
- Microsomal membranes from recombinant CHO cells were prepared and the binding assay made as previously described (Breu V., et al, FEBS Lett 1993; 334:210).
- the assay was performed in 200 uL 50 mM Tris/HCI buffer, pH 7.4, including 25 mM MnC , 1 mM EDTA and 0.5% (w/v) BSA in polypropylene microtiter plates.
- Membranes containing 0.5 ug protein were incubated for 2 h at 20°C with 8 pM [ 125 I]ET-1 (4000 cpm) and increasing concentrations of unlabelled antagonists. Maximum and minimum binding were estimated in samples without and with 100 nM ET-1 , respectively. After 2 h, the membranes were filtered on filterplates containing GF/C filters (Unifilterplates from Canberra Packard S.A. Zurich, Switzerland).
- IC 50 was calculated as the concentration of antagonist inhibiting 50 % of the specific binding of ET-1.
- the IC 50 values obtained with compounds of general formula I are given in Table 1.
- Each ring was suspended in a 10 ml isolated organ bath filled with Krebs- Henseleit solution (in mM; NaCI 115, KCI 4.7, MgSO 4 1.2, KH 2 PO 4 1.5, NaHCO 3 25, CaCI 2 2.5, glucose 10) kept at 37°C and gassed with 95% O 2 and 5% CO 2 .
- the rings were connected to force transducers and isometric tension was recorded (EMKA Technologies SA, Paris, France).
- the rings were stretched to a resting tension of 3 g (aorta) or 2 g (trachea). Cumulative doses of ET-1 (aorta) or sarafotoxin S6c (trachea) were added after a 10 min incubation with the test compound or its vehicle.
- the functional inhibitory potency of the test compound was assessed by calculating the concentration ratio, i.e. the shift to the right of the EC50 induced by different concentrations of test compound.
- EC 50 is the concentration of endothelin needed to get a half-maximal contraction
- pA 2 is the negative logarithm of the antagonist concentration which induces a two-fold shift in the EC 50 value.
- the described compounds can be used for treatment of diseases, which are associated with an increase in vasoconstriction, proliferation or inflammation due to endothelin.
- diseases which are associated with an increase in vasoconstriction, proliferation or inflammation due to endothelin.
- diseases are hypertension, pulmonary hypertension, coronary diseases, cardiac insufficiency, renal and myocardial ischemia, renal failure, cerebral ischemia, dementia, migraine, subarachnoidal hemorrhage, Raynaud's syndrome, digital ulcers and portal hypertension.
- Atherosclerosis restenosis after balloon or stent angioplasty, inflammation, stomach and duodenal ulcer, cancer, melanoma, prostate cancer, prostatic hypertrophy, erectile dysfunction, hearing loss, amaurosis, chronic bronchitis, asthma, pulmonary fibrosis, gram negative septicemia, shock, sickle cell anemia, glomerulonephritis, renal colic, glaucoma, connective tissue diseases, therapy and prophylaxis of diabetic complications, complications of vascular or cardiac surgery or after organ transplantation, complications of cyclosporin treatment, pain, hyperlipidemia as well as other diseases, presently known to be related to endothelin.
- the compounds can be administered orally, rectally, parenterally, e.g. by intravenous, intramuscular, subcutaneous, intrathecal or transdermal administration or sublingually or as ophthalmic preparation or administered as aerosol.
- parenterally e.g. by intravenous, intramuscular, subcutaneous, intrathecal or transdermal administration or sublingually or as ophthalmic preparation or administered as aerosol.
- applications are capsules, tablets, orally administered suspensions or solutions, suppositories, injections, eye-drops, ointments or aerosols/nebulizers.
- Preferred applications are intravenous, intra-muscular, or oral administrations as well as eye drops.
- the dosage used depends upon the type of the specific active ingredient, the age and the requirements of the patient and the kind of application. Generally, dosages of 0.1 - 50 mg / kg body weight per day are considered.
- the preparations with compounds can contain inert or as well pharmacodynamically active excipients. Tablets or granules, for example, could contain a number of binding agents, filling excipients, carrier substances or diluents.
- the present invention relates to pyhmidine-sulfamides of the general formula I,
- R 1 represents lower alkyl-O-(CH2) n -, cycloalkyl-O-(CH 2 ) n -, cycloalkyl-CH 2 -O-(CH 2 ) n -;
- R .2 represents -CH 3 ; R a -Y-(CH 2 ) n
- R 3 represents aryl; heteroaryl;
- R 4 represents hydrogen; thfluoromethyl; lower alkyl; lower alkyl-amino; lower alkyloxy; lower alkyloxy-lower alkyloxy; hydroxy-lower alkyloxy; lower alkyl- sulfinyl; lower alkylthio; lower alkylthio-lower alkyl; hydroxy-lower alkyl; lower alkyloxy-lower alkyl; hydroxy-lower alkyloxy-lower alkyl; hydroxy-lower alkylamino; lower alkylamino-lower alkyl; amino; di-lower alkylamino; [N-(hydroxy-lower alkyl)- N-(lower alkyl)]-amino; aryl; arylamino; aryl-lower alkylamino; arylthio; aryl-lower alkylthio; aryloxy; aryl-lower alkyloxy; aryl-lower alkyl
- X represents oxygen; sulfur; -CH 2 - or a bond;
- Y represents a bond, -O-; -NH-; -SO 2 -NH-; -NH-SO 2 -NH-; -O-CO-; -CO-O-; -O-CO-NH-; -NH-CO-O-; -NH-CO-NH-;
- n represents the integers 2, 3, or 4;
- n represents the integers 2, 3, or 4;
- R a represents aryl, heteroaryl, lower alkyl, cycloalkyl, hydrogen
- lower means straight and branched chain groups with one to seven carbon atoms, preferably 1 to 4 carbon atoms.
- Examples of lower alkyl and lower alkoxy groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, tert.-butyl, pentyl, hexyl, heptyl, methoxy, ethoxy, propoxy, butoxy, iso-butoxy, sec.-butoxy and tert.-butoxy.
- Lower alkylendioxy-groups are preferably methylen-dioxy and ethylen-dioxy groups.
- Examples of lower alkanoyl-groups are acetyl, propanoyl and butanoyl.
- Lower alkenylen means e.g.vinylen, propenylen and butenylen.
- Lower alkenyl and lower alkynyl means groups like ethenyl, propenyl, butenyl, 2- methyl-propenyl, and ethinyl, propinyl, butinyl, pentinyl, 2-methyl-pentinyl.
- Lower alkenyloxy means allyloxy, vinyloxy and propenyloxy.
- cycloalkyl means a saturated cyclic hydrocarbon ring with 3 to 7 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, which may be substituted with lower alkyl, hydroxy-lower alkyl, amino-lower alkyl, and lower alkoxy-lower alkyl groups.
- heterocyclyl means saturated or unsaturated (but not aromatic), four, five-, six- or seven-membered rings containing one or two nitrogen, oxygen or sulfur atoms which may be the same or different and which rings may be adequatly substituted with lower alkyl, lower alkoxy, e.g.
- heteroaryl means six-membered aromatic rings containing one to four nitrogen atoms, benzo-fused six-membered aromatic rings containing one to three nitrogen atoms, five-membered aromatic rings containing one oxygen or one nitrogen or one sulfur atom, benzo-fused five-membered aromatic rings containing one oxygen or one nitrogen or one sulfur atom, five membered aromatic- rings containig an oxygen and nitrogen atom and benzo-fused derivatives thereof, five membered aromatic rings containing a sulfur and a nitrogen atom and benzo fused derivatives thereof, five- membered aromatic rings containing two nitrogen atoms and benzo fused derivatives thereof, five membered aromatic rings containing three nitrogen atoms and benzo fused derivatives thereof or the tetrazolyl ring; e.g.
- aryl represents unsubstituted as well as mono-, di- or tri-substituted aromatic rings with 6 to 10 carbon atoms like phenyl or naphthyl rings which may be substituted with aryl, halogen, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, lower alkenyloxy, lower alkynyl-lower alkyl-oxy, lower alkenylen, lower alkylenoxy or lower alkylendioxy forming with the phenyl ring a five- or six-membered ring, hydroxy-lower alkyl, hydroxy-lower alkenyl, hydroxy- lower alkyl-lower alkynyl, lower alkyloxy-lower alkyl, lower alkyloxy-lower alkyloxy, trifluoromethyl, trifluoromethoxy, cycloalkyl, hydroxy-cycloalkyl, heterocyclyl, hetero
- salts encompasses either salts with inorganic acids or organic acids like hydrohalogenic acids, e.g. hydrochloric or hydrobromic acid; sulfuric acid, phosphoric acid, nitric acid, citric acid, formic acid, acetic acid, maleic acid, tartaric acid, methylsulfonic acid, p- toluolsulfonic acid and the like or in case the compound of formula I is acidic in nature with an inorganic base like an alkali or earth alkali base, e.g. sodium hydroxide, potassium hydroxide, calcium hydroxide and the like.
- hydrohalogenic acids e.g. hydrochloric or hydrobromic acid
- an inorganic base like an alkali or earth alkali base,
- the compounds of the general formula I might have one or more asymmetric carbon atoms and may be prepared in form of optically pure enantiomers or diastereomers, mixtures of enantiomers or diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates and also in the meso-form.
- the present invention encompasses all these forms. Mixtures may be separated in a manner known per se, i.e. by column chromatography, thin layer chromatography, HPLC or crystallization.
- the described compounds of the general formula I and their pharmaceutically acceptable salts may be used for treatment of diseases which are associated with an increase in vasoconstriction, proliferation or inflammation due to endothelin.
- diseases which are associated with an increase in vasoconstriction, proliferation or inflammation due to endothelin.
- diseases are hypertension, coronary diseases, cardiac insufficiency, renal and myocardial ischemia, renal failure, cerebral ischemia, dementia, migraine, subarachnoidal hemorrhage, Raynaud's syndrome, portal hypertension, and pulmonary hypertension.
- compositions can also be used for the treatment or prevention of atherosclerosis, restenosis after balloon or stent angioplasty, inflammation, stomach and duodenal ulcer, cancer, prostatic hypertrophy, erectile dysfunction, hearing loss, amaurosis, chronic bronchitis, asthma, gram negative septicemia, shock, sickle cell anemia, glomerulonephritis, renal colic, glaucoma, therapy and prophylaxis of diabetic complications, complications of vascular or cardiac surgery or after organ transplantation, complications of cyclosporin treatment, pain, hyperlipidemia as well as other diseases presently known to be related to endothelin.
- These compositions may be administered in enteral or oral form e.g.
- compositions may contain the compounds of formula I as well as their pharmaceutically acceptable salts in combination with inorganic and/or organic excipients which are usual in the pharmaceutical industry like lactose, maize or derivatives thereof, talcum, stearinic acid or salts of these materials.
- vegetable oils, waxes, fats, liquid or half-liquid polyols may be used.
- solutions and sirups e.g. water, polyols, saccharose, glucose can be used.
- injectables can be prepared by using e.g. water, polyols, alcohols, glycerin, vegetable oils, lecithin, or liposomes.
- Suppositories may be prepared by using natural or hydrogenated oils, waxes, fatty acids (fats), liquid or half-liquid polyols.
- compositions may contain in addition preservatives, stability improving substances, viscosity improving or regulating substances, solubility improving substances, sweeteners, dyes, taste improving compounds, salts to change the osmotic pressure, buffer or anti-oxidants.
- the compounds of general formula I may also be used in combination with one or more other therapeutically useful substances e.g. ⁇ - and ⁇ -blockers like phentolamine, phenoxybenzamine, atenolol, propranolol, timolol, metoprolol, carteolol and the like; vasodilators like hydralazine, minoxidil, diazoxide, or flosequinan; calcium-antagonists like diltiazem, nicardipine, nimodipine, verapamil or nifedipine; ACE-inhibitors like cilazapril, captopril, enalapril, lisinopril and the like; potassium channel activators like pinacidil; angiotensin II receptor antagonists like losartan, valsartan, irbesartan and the like; diuretics like hydrochlorothiazide, chlorothiazide
- the dosage may vary within wide limits but should be adapted to the specific situation.
- the dosage given daily in oral form should be between about 3 mg and about 3 g, preferably between about 10 mg and about 1 g, especially preferred between 5 mg and 300 mg, per adult with a body weight of about 70 kg.
- the dosage should be administered preferably in 1 to 3 doses per day which are of equal weight. As usual children should receive lower doses which are adapted to body weight and age.
- Preferred compounds are compounds of general formula I wherein R 3 represents phenyl, mono- or di-substituted phenyl substituted with ethoxy, methoxy or chlorine and X represents oxygen, and pharmaceutically acceptable salts thereof.
- a second group of preferred compounds of general formula I are those wherein R 3 represents phenyl, mono- or di-substituted phenyl substituted with ethoxy, methoxy or chlorine, X represents oxygen and R 2 represents -(CH 2 )m-Y-R a . and pharmaceutically acceptable salts thereof.
- a third group of preferred compounds of general formula I are those wherein R 3 represents phenyl, mono- or di-substituted phenyl substituted with ethoxy, methoxy or chlorine, X represents oxygen and R 2 represents -(CH 2 ) 2 -O-R a , with R a being heteroaryl, and pharmaceutically acceptable salts thereof.
- R 1 , R 2 , R 3 and R 4 are as defined in general formula I above, and pharmaceutically acceptable salts of compounds of formula II. Also preferred are compounds of formula
- R 1 , R 2 and R 4 are as defined in general formula I above and A represents hydrogen, methyl, ethyl, chlorine, bromine, fluorine, trifluoromethyl, or methoxy, and pharmaceutically acceptable salts of compounds of formula III.
- R 1 , R 4 and m are as defined in general formula I above and A is as defined in formula III above and R 5 represents aryl or heteroaryl, and pharmaceutically acceptable salts of compounds of formula IV.
- Another especially preferred group of compounds are compounds of formula V
- R 1 is as defined in general formula I above, A is as defined in formula III above and R 5 represents aryl or heteroaryl, and pharmaceutically acceptable salts of compounds of formula V.
- Especially preferred compounds among the group of compounds of formula V are those wherein R 5 represents substituted pyrimidine, and pharmaceutically acceptable salts thereof.
- Another group of preferred compounds are compounds of general formula I, wherein R represents CH 3 -O-CH 2 CH 2 -, R 6 represents hydrogen and R 2 , R 3 , and R 4 are as defined in general formula I, and pharmaceutically acceptable salts of compounds thereof.
- Another group of preferred compounds are compounds of formula V wherein R 1 represents CH 3 -O-CH 2 CH 2 -, A is as defined in formula III above and R 5 represents aryl, or heteroaryl, and pharmaceutically acceptable salts of compounds of formula V
- Particularly preferred compounds are:
- the desired compounds of general formula I can be prepared by reacting a compound of the formula 1 :
- G 1 is a reactive residue, preferentially a chlorine atom, and the other symbols are as defined in general formula I above, with a compound of the formula 2:
- R 5 2 is as defined in general formula I above, or a salt thereof.
- the compounds of general formula I may also be prepared by reacting a compound of formula 3:
- G is a reactive residue, preferentially a halogen atom, and R is the same as defined in formula IV above.
- the compounds of general formula I may also be prepared by reacting a compound of the formula 5:
- G 3 is a lower alkylsulfonyl group or a phenylsulfonylgroup or a halogen atom, and the other symbols are the same as described in general formula I above, or a salt thereof, with a compound of the formula 6:
- R 4 represents:
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BR0316724-0A BR0316724A (en) | 2002-12-02 | 2003-11-10 | Compounds, use of one or more compounds, and process for the manufacture of pharmaceutical compositions |
EP03778307A EP1569914B1 (en) | 2002-12-02 | 2003-11-10 | Pyrimidine-sulfamides and their use as endothelian receptor antagonist |
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EP0213601 | 2002-12-02 | ||
EP02103601 | 2002-12-02 | ||
PCT/EP2003/012502 WO2004050640A1 (en) | 2002-12-02 | 2003-11-10 | Pyrimidine-sulfamides and their use as endothelian receptor antagonist |
EP03778307A EP1569914B1 (en) | 2002-12-02 | 2003-11-10 | Pyrimidine-sulfamides and their use as endothelian receptor antagonist |
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EP1569914B1 EP1569914B1 (en) | 2009-02-18 |
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EP03778307A Expired - Lifetime EP1569914B1 (en) | 2002-12-02 | 2003-11-10 | Pyrimidine-sulfamides and their use as endothelian receptor antagonist |
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US (1) | US7452896B2 (en) |
EP (1) | EP1569914B1 (en) |
JP (1) | JP4769460B2 (en) |
KR (1) | KR101063042B1 (en) |
CN (1) | CN100379730C (en) |
AT (1) | ATE423103T1 (en) |
AU (1) | AU2003285321B2 (en) |
BR (1) | BR0316724A (en) |
CA (1) | CA2507334C (en) |
DE (1) | DE60326263D1 (en) |
ES (1) | ES2320649T3 (en) |
IL (1) | IL168836A (en) |
MX (1) | MXPA05005793A (en) |
NO (1) | NO20052520L (en) |
NZ (1) | NZ540937A (en) |
RU (1) | RU2329255C2 (en) |
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ZA (1) | ZA200505109B (en) |
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KR100739367B1 (en) | 2004-07-14 | 2007-07-16 | 크리스탈지노믹스(주) | Sulfamide derivatives and pharmaceutical composition for upregulation of lipid metabolism containing same |
TW200628467A (en) * | 2004-11-11 | 2006-08-16 | Actelion Pharmaceuticals Ltd | Novel sulfamides |
US7887824B2 (en) | 2004-11-30 | 2011-02-15 | L'oreal | Sulfamide derivatives and cosmetic use thereof |
FR2878523B1 (en) * | 2004-11-30 | 2007-09-14 | Oreal | NOVEL SULFAMID DERIVATIVES AND THEIR COSMETIC USE |
US8168588B2 (en) * | 2005-01-25 | 2012-05-01 | Five Prime Therapeutics, Inc. | Compositions comprising FGF-9 and betacellulin and methods for treating cardiac conditions |
US20100100372A1 (en) * | 2007-01-26 | 2010-04-22 | Panasonic Corporation | Stereo encoding device, stereo decoding device, and their method |
CA2682849C (en) * | 2007-04-03 | 2012-05-29 | Pfizer Inc. | Sulfonamides and pharmaceutical compositions thereof |
MX2010001837A (en) * | 2007-08-17 | 2010-03-10 | Actelion Pharmaceuticals Ltd | Iron with actively cooled soleplate and method for cooling the soleplate. |
US20110263623A1 (en) * | 2008-08-12 | 2011-10-27 | Cadila Healthcare Limited | Process for preparation of bosentan |
NO2315587T3 (en) | 2008-08-13 | 2018-03-24 | ||
CN103724281A (en) * | 2013-12-03 | 2014-04-16 | 镇江圣安医药有限公司 | Novel derivative of N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'-propyl and application of novel derivative |
US11319305B2 (en) * | 2017-11-21 | 2022-05-03 | Shijiazhuang Sagacity New Drug Development Co., Ltd. | Pyrimidine sulfamide derivative and preparation method and medical application thereof |
CN108997223B (en) * | 2018-08-09 | 2020-06-30 | 浙江先锋科技股份有限公司 | Preparation method of 5- (4-bromophenyl) -4, 6-dichloropyrimidine |
CN109232546B (en) * | 2018-09-25 | 2020-09-04 | 中国人民解放军总医院 | Medical application of pyrimidine sulfonamide derivative |
RU2763899C1 (en) * | 2021-03-26 | 2022-01-11 | федеральное государственное бюджетное учреждение «Национальный медицинский исследовательский центр онкологии» Министерства здравоохранения Российской Федерации | Sodium salt of 4-{ 2-[2-(4- hydroxy-3-methoxyphenyl)-vinyl]-6-ethyl-4-oxo-5-phenyl-4h-pyrimidine-1-yl} -benzenesulfamide, which has an antitumor effect |
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FR1549494A (en) | 1967-10-31 | 1968-12-13 | ||
DE2801584A1 (en) * | 1978-01-14 | 1979-07-19 | Bayer Ag | HALOGEN-SUBSTITUTED PYRIMIDIN (2) YL-THIONO-THIOL-PHOSPHOR (PHOSPHONE) - ACID ESTERS, PROCESS FOR THEIR PRODUCTION AND THEIR USE AS INSECTICIDES AND ACARICIDES |
RU2086544C1 (en) | 1991-06-13 | 1997-08-10 | Хоффманн-Ля Рош АГ | Benzenesulfonamide derivatives of pyrimidine or their salts, pharmaceutical composition for treatment of diseases associated with endothelin activity |
TW394761B (en) | 1993-06-28 | 2000-06-21 | Hoffmann La Roche | Novel Sulfonylamino Pyrimidines |
IL111959A (en) | 1993-12-17 | 2000-07-16 | Tanabe Seiyaku Co | N-(polysubstituted pyrimidin-4-yl) benzenesulfonamide derivatives their preparation and pharmaceutical compositions containing them |
TW313568B (en) | 1994-12-20 | 1997-08-21 | Hoffmann La Roche | |
US5739333A (en) | 1995-05-16 | 1998-04-14 | Tanabe Seiyaku Co., Ltd. | Sulfonamide derivative and process for preparing the same |
JP3013752B2 (en) * | 1995-05-16 | 2000-02-28 | 田辺製薬株式会社 | Sulfonamide derivative |
ATE201202T1 (en) | 1995-12-20 | 2001-06-15 | Yamanouchi Pharma Co Ltd | ARYLETHENESULFONAMIDE DERIVATIVES AND MEDICATIONS CONTAINING SAME |
TWI284642B (en) * | 1999-01-18 | 2007-08-01 | Hoffmann La Roche | Novel heterocyclic sulfonamides |
DE60118782T2 (en) | 2000-12-18 | 2007-01-25 | Actelion Pharmaceuticals Ltd. | NEW SULFAMIDES AND THEIR USE AS ENDOTHELIN ANTAGONISTS |
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Also Published As
Publication number | Publication date |
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KR101063042B1 (en) | 2011-09-07 |
CN1711248A (en) | 2005-12-21 |
CN100379730C (en) | 2008-04-09 |
AU2003285321A1 (en) | 2004-06-23 |
IL168836A (en) | 2010-12-30 |
RU2329255C2 (en) | 2008-07-20 |
US7452896B2 (en) | 2008-11-18 |
ATE423103T1 (en) | 2009-03-15 |
NO20052520L (en) | 2005-06-27 |
NO20052520D0 (en) | 2005-05-25 |
WO2004050640A1 (en) | 2004-06-17 |
US20070167472A1 (en) | 2007-07-19 |
KR20050086625A (en) | 2005-08-30 |
BR0316724A (en) | 2005-10-18 |
ES2320649T3 (en) | 2009-05-27 |
MXPA05005793A (en) | 2005-08-16 |
DE60326263D1 (en) | 2009-04-02 |
JP2006509775A (en) | 2006-03-23 |
CA2507334C (en) | 2013-05-07 |
ZA200505109B (en) | 2007-04-25 |
CA2507334A1 (en) | 2004-06-17 |
JP4769460B2 (en) | 2011-09-07 |
EP1569914B1 (en) | 2009-02-18 |
RU2005120769A (en) | 2006-02-27 |
AU2003285321B2 (en) | 2010-04-08 |
NZ540937A (en) | 2008-06-30 |
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